The bacterial endotoxin (lipopolysaccharide, LPS) can trigger systemic hyper-inflammatory response that subsequently leads to multiple organ dysfunction syndrome. LPS binding to toll-like receptor 4 (TLR4) induces the activation of mitogen-activated protein kinase (MAPK) and nuclear factor (B (NF-(B) resulting in production of pro-inflammatory cytokines. When this production becomes uncontrolled and excessive, it leads to the development of septic shock. p120-catenin, a component of adherens junctions in endothelial cells and other polarized adherent cells, has recently been implicated in the intrinsic regulation of inflammation. p120-catenin null epidermal cells exhibited increased activity of NF-(B and proinflammatory NF-(B targets. In preliminary experiments, we made the intriguing observation that deletion of p120 in the lung vasculature with specific siRNA rendered the mice highly susceptible to LPS, suggesting that p120 is a crucial element of the host response to sepsis. Our supporting data further demonstrate that p120-catenin expression in the mouse lung is rapidly reduced after LPS challenge. Also, deletion of p120-catenin in pulmonary vasculature endothelium and cultured pulmonary microvascular endothelial cells significantly increased LPS-induced expression of intercellular adhesion molecule-1 (ICAM-1), neutrophil adhesion, and transendothelial neutrophil migration via activation of NF-(B and MAPK signaling. Collectively, these data suggest that p120-catenin serves to dampen the LPS-induced inflammatory response in lungs. The objectives of the proposed studies are to define the anti-inflammatory role of p120-catenin, determine the mechanism of p120-catenin degradation induced by LPS, and to explore the possibility that p120-catenin interferes with the TLR4-activated signaling pathway to mitigate lung inflammatory injury. The proposal will address the following Specific Aims: 1. To determine the mechanisms of regulation of pulmonary endothelial p120-catenin expression in response to LPS-induced lung injury. Here we will dissect the signaling pathways that cause the loss of p120 in the pulmonary microvasculature following LPS challenge. 2. To define the role of endothelial p120-catenin expression in the regulation of LPS-induced lung inflammatory injury. 3. To identify the signaling pathways by which endothelial p120 regulates TLR4 signaling-mediated lung inflammation. The identification of p120-catenin-activated pathways modulating LPS-induced sepsis will be of great interest in the design of therapeutic strategies for the treatment or prevention of acute lung injury.